Hypercholesterolemia is considered to be the uppermost risk factor for ischemic cardiovascular diseases such as arteriosclerosis and coronary disease. Compounds such as mevastatin, lovastatin, pravastatin and simvastatin reduce biosynthesis of cholesterol in human by inhibiting the first rate-limiting enzyme, HMG-CoA reductase, in the biosynthesis of cholesterol, and are therefore widely used as agents for reducing cholesterol concentration in plasma. This class of compounds is referred to as statin compounds, which are present in the form of lactones as shown in formula I, or in the form of dihydroxy acids with open ring structures as shown in formula II.
                wherein Z represents H, ammonium, or a metal cation,        R1 is H or CH3,        R2 is CH3 or OH.        
The statin compounds are generally administered to a patient in the form of lactones, and then hydrolysed to active metabolites in the form of dihydroxy acids. As a result, there exists a need for development of methods for preparing statin compounds by lactonization. Lactonization is an equilibrium process. In order to obtain a high yield of the lactones, particular methods have to be employed to shift the equilibrium to the lactone side of the equation:Dihydroxy acid (or ammonium salt, metal salt thereof)Lactone+H2O (+NH3 or metal cation)
U.S. Pat. Nos. 4,444,784, 4,582,915, 4,820,850, U.S. Pat. No. 6,307,066B1, and U.S. Pat. No. 6,797,381B2 disclose that the equilibrium is shifted to the lactone side of the equation by azeotropic distillation or introducing an inert gas flow to the hot reaction solvent so as to remove water or ammonia.
All of the above methods have disadvantages, such as high reaction temperatures and long reaction times. Since dihydroxy acids are sensitive to heat, high temperature and longer reaction time will lead to formation of a dimer impurity resulting from a further esterification reaction between 3-hydroxyl group of the lactone and the free dihydroxy acids, and thus the overall output and purity of lactones are decreased. Since the acceptable impurity level of dimers should be less than 0.2%, the above methods are not beneficial to the preparation of statin compounds with high purity.
U.S. Pat. No. 4,916,239 discloses a method for converting a dihydroxy acid or salt thereof into a lactone in a water miscible solvent (especially acetic acid medium) by use of a strong acid catalyst. After a period of reaction time, an appropriate amount of water is added to the reaction mixture to isolate the insoluble lactone, thereby shifting the equilibrium to generate subsequent lactones. This method eliminates the need of high temperature, and decreases the amount of dimmer impurities. However, this method needs 1.2-1.5 moles of strong acid such as methanesulfonic acid, sulphuric acid and trifluoroacetic acid, and therefore needs a large amount of strong base for neutralization and tedious post-processing. As a result, the method is not suitable for industrial scale production and is harmful to the environment. In addition, completion of lactonization requires addition of extra water, which leads to a further crystallization on the formed crystal, and results in heterogeneity of lactone structure and lower purity. Meanwhile, too quick or premature addition of water and inappropriate amount of water lead to an incomplete reaction, lengthen reaction time and post-processing time to up to 9-12 hours, which decreases production efficiency.
U.S. Pat. No. 6,562,984 discloses that water generated during the lactonization reaction between the lactonization agent, methanesulfonic acid, and dihydroxy acid or a salt thereof is allowed to form a hydrated complex in the solvent CH2Cl2. Since the hydrated complex is substantially insoluble in the solvent, it can be removed by filtration. However, the method requires a strict anhydrous condition, the solvent CH2Cl2 requires anhydrous treatment prior to use, and the agent methanesulfonic acid should also be anhydrous. In addition, the reaction requires a CaCl2 drying tube to isolate and absorb the moisture in the air, needs to be protected by introducing nitrogen gas, and is strict with reaction devices and operations. Moreover, the complex of by-product methanesulfonic ammonium generated after the reaction and water is relatively viscous, and is difficult to be filtrated, which have some effects on the environment and operations.
Therefore, there exists a need for novel methods for preparing statin compounds by lactonization.